Hyperactivated mononuclear phagocytes, type II interferon and cytotoxic T cells with restricted clonal repertoire underly SARS-CoV2 related multisystem inflammatory syndrome in children

In rare instances, children with a recent history of Sars-CoV2 infection develop a novel immunodysregulation syndrome called multisystem inflammatory syndrome in children or MIS-C. In this study, we set out to investigate the immunopathology of MIS-C and compared this to the hyperinflammatory disease associated with severe SARS-CoV2 infection in adults. Analyzing biomarkers of organ damage, we established that MIS-C does not result in respiratory epithelial damage but is associated with vascular endothelitis and gastrointestinal epithelial cell injury. We observed a strong humoral response against Sars-CoV2 in MIS-C patients, including B cell population expansion and a convalescent antibody repertoire. Measuring cytokine responses, innate immune cells and complement cascade, we found an inflammatory signature unique to MIS-C. ScRNA-seq analysis revealed IFNg as an upstream cytokine and we identified highly activated NK cells and ab T cells expressing TIM3, a marker of IFNg effectors. ScRNA-seq characterized these ab T cells as an IFNg producing, actively proliferating and metabolically adapted population with cytotoxic potential. TCR profiling revealed that in all MIS-C patients many of the activated TIM3+ lymphocytes uniquely express TRBV11.2 in combination with promiscuous a receptor usage, indicating a superantigenic response. Upon response to treatment, normalization of innate cytokines was paralleled by contraction of patrolling monocytes, neutrophils and TIM3+ lymphocytes, suggesting a central role for these cells and IFNg in disease pathogenesis